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Open access

Eleanor P Thong, Sarah Catford, Julie Fletcher, Phillip Wong, Peter J Fuller, Helena Teede and Frances Milat

Summary

The association between type 1 diabetes mellitus (T1DM) and bone health has garnered interest over the years. Fracture risk is known to be increased in individuals with T1DM, although bone health assessment is not often performed in the clinical setting. We describe the case of a 21-year-old male with longstanding T1DM with multilevel vertebral fractures on imaging, after presenting with acute back pain without apparent trauma. Dual-energy X-ray absorptiometry (DXA) revealed significantly reduced bone mineral density at the lumbar spine and femoral neck. Extensive investigations for other secondary or genetic causes of osteoporosis were unremarkable, apart from moderate vitamin D deficiency. High-resolution peripheral quantitative computed tomography and bone biospy revealed significant alterations of trabecular bone microarchitecture. It later transpired that the patient had sustained vertebral fractures secondary to unrecognised nocturnal hypoglycaemic seizures. Intravenous zoledronic acid was administered for secondary fracture prevention. Despite anti-resorptive therapy, the patient sustained a new vertebral fracture after experiencing another hypoglycaemic seizure in his sleep. Bone health in T1DM is complex and not well understood. There are significant challenges in the assessment and management of osteoporosis in T1DM, particularly in young adults, where fracture prediction tools have not been validated. Clinicians should be aware of hypoglycaemia as a significant risk factor for fracture in patients with T1DM.

Learning points:

  • Type 1 diabetes mellitus (T1DM) is a secondary cause of osteoporosis, characterised by reduced bone mass and disturbed bone microarchitecture.

  • Hypoglycaemic seizures generate sufficient compression forces along the thoracic column and can cause fractures in individuals with compromised bone quality.

  • Unrecognised hypoglycaemic seizures should be considered in patients with T1DM presenting with fractures without a history of trauma.

  • Patients with T1DM have increased fracture risk and risk factors should be addressed. Evaluation of bone microarchitecture may provide further insights into mechanisms of fracture in T1DM.

  • Further research is needed to guide the optimal screening and management of bone health in patients with T1DM.

Open access

Hans-Christof Schober, Christian Kneitz, Franziska Fieber, Kathrin Hesse and Henry Schroeder

Summary

Tumor-induced osteomalacia (TIO) is caused by the hormone fibroblast growth factor 23 (FGF-23). It is mainly produced in the tissue of mesenchymal tumors. Patients with TIO frequently suffer from a chronic decompensated pain syndrome and/or muscle weakness with postural deformity. Despite the severity of the disease, the diagnosis is frequently established late. In some cases, it takes several years to establish the condition. This case report concerning a 68-year old woman demonstrates the selective blood sampling for FGF-23 as path-breaking diagnostics to confirm the diagnosis of a neuroendocrine tumor.

Learning points:

  • Tumor-induced osteomalacia is a rare condition compared to other paraneoplastic syndromes.

  • It causes complex symptoms such as progressive reduction of physical capacity, exhaustion, fatigue, a decompensated pain syndrome of the musculoskeletal system and fractures of several bones.

  • Elevated serum levels of FGF-23 implicate massive phosphate elimination and resulting hypophosphatemia.

  • The diagnosis is often established over a period of several years because the localization of small FGF-23-producing tumors is complicated.

  • It is the combination of MRI and selective blood sampling for FGF-23 which permits reliable identification of tumors causing TIO and leads to accurate localization.

  • In a patient with generalized pain and reduced physical capacity, osteological parameters such as phosphate, 25-OH vitamin D3 and 1,25-(OH)2D3, as well as bone-specific alkaline phosphatase levels in serum should be determined. Hypophosphatemia should always lead to further diagnostic investigations aiming at the detection of an FGF-23-producing tumor.

Open access

B Cangiano, C Cacciatore, L Persani and M Bonomi

We describe a case of severe erythrocytosis caused by testosterone replacement therapy in a 66-year-old man affected with hypogonadotropic hypogonadism (HH) determining osteoporosis, resolved by switching to restoration therapy with clomiphene citrate. The patient complained fatigue, loss of libido and defective erections and a spontaneous vertebral fracture despite bisphosphonate therapy and vitamin D supplementation. The examinations proved isolated HH and he was therefore treated with testosterone gel with regression of specific manifestations but elevated hemoglobin and hematocrit values. Therefore, it was decided to switch to a restoration therapy with clomiphene citrate 25 mg/die, which resulted in the resolution of symptoms without evident side effects. In a couple of months, the patient showed normalization of testosterone levels and increment of testicular volume. Since secondary hypogonadism is the consequence of an insufficient stimulation of the gonads by hypothalamic–pituitary axis, therapeutic approaches aimed to restore endogenous testosterone production should be considered in alternative to testosterone replacement, particularly if side effects intervene. Among these strategies, clomiphene citrate seems to have a high efficacy and safety profile also in the elderly with isolated HH and no evident pituitary lesion.

Learning points:

  • Hypogonadism should always be assessed in patients with severe loss in BMD and undergo appropriate medical treatment.

  • In hypogonadotropic hypogonadism, more approaches are available other than testosterone replacement therapy alone.

  • In patients with severe late-onset central hypogonadism presenting with erythrocytosis even at low doses of replacement therapy, restoration therapy with clomiphene could prove to be an effective solution, particularly in patients with a reversible disruption of GNRH/gonadotropin functions.

  • Clomiphene citrate increases gonadotropin levels and testicular volume and should therefore be considered in hypogonadal men who wish to remain fertile.

Open access

Ayanthi A Wijewardene, Sarah J Glastras, Diana L Learoyd, Bruce G Robinson and Venessa H M Tsang

Summary

Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour that originates from the parafollicular cells of the thyroid gland. The most common presentation of MTC is with a single nodule; however, by the time of diagnosis, most have spread to the surrounding cervical lymph nodes. Cushing’s syndrome is a rare complication of MTC and is due to ectopic adrenocorticotrophic hormone (ACTH) secretion by tumour cells. Cushing’s syndrome presents a challenging diagnostic and management issue in patients with MTC. Tyrosine kinase inhibitors (TKI) previously used for the management of metastatic MTC have become an important therapeutic option for the management of ectopic ACTH in metastatic MTC. The article describes three cases of ectopic ACTH secretion in MTC and addresses the significant diagnostic and management challenges related to Cushing’s syndrome in metastatic MTC.

Learning points:

  • Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour.

  • Cushing’s syndrome is a rare complication of MTC that has a significant impact on patients’ morbidity and mortality.

  • Tyrosine kinase inhibitors (TKI) provide an important therapeutic option for the management of ectopic ACTH in metastatic MTC.

Open access

Catarina Roque, Ricardo Fonseca, Carlos Tavares Bello, Carlos Vasconcelos, António Galzerano and Sância Ramos

Summary

Primary adrenal lymphoma is a rare malignancy. It frequently presents bilaterally and with symptoms of adrenal insufficiency. Amiodarone may induce secondary organ dysfunction, and thyrotoxicosis develops in 15% of cases. The symptomatology of both conditions is nonspecific, especially in the elderly, and a high suspicion index is necessary for appropriate diagnosis. A 78-year-old female presented to the emergency department with confusion, nausea and vomiting. She had recently been to the emergency department with urinary tract infection, vomiting and acute hypochloremic hyponatremia. Upon re-evaluation, the leukocyturia persisted and because of TSH 0.01 µU/mL and free-T4 68 (10–18) pmol/L, she was admitted to the Endocrinology ward. Further evaluation supported amiodarone-induced thyroiditis type 2. Sepsis ensued, in the setting of nosocomial pneumonia. Hemodynamic instability, hyponatremia, hypoglycemia and vomiting raised the suspicion of adrenocortical insufficiency. Fluid resuscitation and hydrocortisone led to clinical improvement, and adrenal insufficiency was admitted. The thoracoabdominal tomography suggested an endobronchic primary lesion with hepatic and adrenal secondary deposits (6.6 and 7 cm), but this was confirmed neither on pleural effusion nor on bronchofibroscopic fluid analyses. The adrenals were not accessible for biopsy. Despite high-dose hydrocortisone maintenance, the patient died before definite diagnosis. The autopsy confirmed primary non-Hodgkin lymphoma.

Learning points:

  • Primary adrenal lymphoma is a rare cause of adrenal insufficiency, but progression can be fast and fatal.

  • Hyperpigmentation is frequently absent.

  • The presenting symptoms are nonspecific and might mimic infection. Disproportion of the general state with signs of specific organ symptomatology is a diagnostic clue.

  • Infection may precipitate adrenal crisis and worsen thyroid function with further adrenal insufficiency exacerbation.

  • In the context of thyrotoxicosis, there may be little clinical response to a therapeutic trial with standard dose glucocorticoids.

  • High-dose glucocorticoid substitution may be required to achieve clinical stability in thyrotoxic patients.

Open access

Davi da Silva Barbirato, Mariana Fampa Fogacci, Mariana Arruda, Monique Oliveira Rodrigues and Leonardo Vieira Neto

Summary

Osteopetrosis (OP) comprehends a rare group of conditions, presenting on radiographs increased bone density, deriving from irregularities in osteoclast differentiation or function. In the autosomal dominant osteopetrosis (ADO), some patients stay asymptomatic for some time, or only develop mild symptoms. The dental surgeon is often the first to presuppose the disease during routine imaging examinations, referring the patient to a specialized medical group. Furthermore, osteomyelitis is one of the major OP complications, and should be refrained through frequent dental monitoring. Signals of cortical interruption, sclerotic sequestra or periosteal new bone formation, should be looked for in these patients. Their dental management is complex and procedures encompassing bone tissue, such as implant procedures, tissue regenerations, tooth extractions, maxillofacial surgeries and orthodontic treatments, when elected, should be avoided. This case report describes a case of ADO with a diagnosis of moderate generalized chronic periodontitis, not statistically related to plaque index. This is the first case to describe such a condition, in which the systemic component and the altered bone metabolism seem to be related to the loss of periodontal apparatus, independent of the biofilm. Concerning prevention, we can reinforce the need for frequent dental monitoring to avoid further interventions in those cases.

Learning points:

  • This paper reports a case in which the systemic component and the altered bone metabolism seem to have been related to the loss of periodontal attachment apparatus, independent of the biofilm.

  • The periodontal damage observed in the OP patient was not related to the dental plaque, which leads us to suggest that the cases of periodontitis in OP patients should be diagnosed as periodontitis as a manifestation of systemic diseases.

  • The periodontitis prevention should be longed for in OP patients thus, we propose that doctors responsible for patients with OP refer them to a dental service as soon as possible and that dentists should be aware of the preventive dentistry value as well as the most appropriate dental management for those cases.

Open access

Peter Taylor, Sasan Dehbozorgi, Arshiya Tabasum, Anna Scholz, Harsh Bhatt, Philippa Stewart, Pranav Kumar, Mohd S Draman, Alastair Watt, Aled Rees, Caroline Hayhurst and Stephen Davies

Summary

Hyponatraemia is the most commonly encountered electrolyte disturbance in neurological high dependency and intensive care units. Cerebral salt wasting (CSW) is the most elusive and challenging of the causes of hyponatraemia, and it is vital to distinguish it from the more familiar syndrome of inappropriate antidiuretic hormone (SIADH). Managing CSW requires correction of the intravascular volume depletion and hyponatraemia, as well as mitigation of on-going substantial sodium losses. Herein we describe a challenging case of CSW requiring large doses of hypertonic saline and the subsequent substantial benefit with the addition of fludrocortisone.

Learning points:

  • The diagnosis of CSW requires a high index of suspicion. Distinguishing it from SIADH is essential to enable prompt treatment in order to prevent severe hyponatraemia.

  • The hallmarks of substantial CSW are hyponatraemia, reduced volume status and inappropriately high renal sodium loss.

  • Substantial volumes of hypertonic saline may be required for a prolonged period of time to correct volume and sodium deficits.

  • Fludrocortisone has a role in the management of CSW. It likely reduces the doses of hypertonic saline required and can maintain serum sodium levels of hypertonic saline.

Open access

Teresa Rego, Fernando Fonseca, Stéphanie Espiard, Karine Perlemoine, Jérôme Bertherat and Ana Agapito

Summary

PBMAH is a rare etiology of Cushing syndrome (CS). Familial clustering suggested a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene. A 70-year-old female patient was admitted due to left femoral neck fracture in May 2014, in Orthopedics Department. During hospitalization, hypertension (HTA) and hypokalemia were diagnosed. She presented with clinical signs of hypercortisolism and was transferred to the Endocrinology ward for suspected CS. Laboratory workup revealed: ACTH <5 pg/mL; urinary free cortisol (UFC), 532 µg/24 h (normal range: 20–90); failure to suppress the low-dose dexamethasone test (0.5 mg every 6 h for 48 h): cortisol 21 µg/dL. Abdominal magnetic resonance imaging (MRI) showed enlarged nodular adrenals (right, 55 × 54 × 30 mm; left, 85 × 53 × 35 mm), and she was submitted to bilateral adrenalectomy. In 2006, this patient’s 39-year-old daughter had been treated by one of the authors. She presented with severe clinical and biological hypercortisolism. Computed tomography (CT) scan showed massively enlarged nodular adrenals with maximal axis of 15 cm for both. Bilateral adrenalectomy was performed. In this familial context of PBMAH, genetic study was performed. Leucocyte DNA genotyping identified in both patients the same germline heterozygous ARMC5 mutation in exon 1 c.172_173insA p.I58Nfs*45. The clinical cases herein described have an identical phenotype with severe hypercortisolism and huge adrenal glands, but different ages at the time of diagnosis. Current knowledge of inheritance of this disease, its insidious nature and the well-known deleterious effect of hypercortisolism favor genetic study to timely identify and treat these patients.

Learning points:

  • PBMAH is a rare etiology of CS, characterized by functioning adrenal macronodules and variable cortisol secretion.

  • The asymmetric/asynchronous involvement of only one adrenal gland can also occur, making disease diagnosis a challenge.

  • Familial clustering suggests a genetic cause that was recently confirmed, after identification of inactivating germline mutations in armadillo repeat-containing 5 (ARMC5) gene.

  • The insidious nature of this disease and the well-known deleterious effect of hypercortisolism favor genetic study of other family members, to diagnose and treat these patients timely.

  • As ARMC5 is expressed in many organs and recent findings suggest an association of PBMAH and meningioma, a watchful follow-up is required.

Open access

Roberto Attanasio, Liana Cortesi, Daniela Gianola, Claudia Vettori, Fulvio Sileo and Roberto Trevisan

Summary

Cushing’s syndrome is associated with increased morbidity and mortality. Although surgery is the first-line treatment, drugs can still play a role as an ancillary treatment to be employed while waiting for surgery, after unsuccessful operation or in patients unsuitable for surgery. We were asked to evaluate a 32-year-old male waiting for cardiac transplantation. Idiopathic hypokinetic cardiomyopathy had been diagnosed since 6 years. He was on treatment with multiple drugs, had a pacemaker, an implantable cardioverter and an external device for the support of systolic function. Physical examination showed severely impaired general status, signs of hypercortisolism and multiple vertebral compression fractures. We administered teriparatide, and the few evaluable parameters supported the diagnosis of ACTH-dependent hypercortisolism: serum cortisol was 24.2 µg/dL in the morning and 20.3 µg/dL after overnight 1 mg dexamethasone, urinary free cortisol (UFC) was 258 µg/24 h and ACTH 125 pg/mL. Pituitary CT was negative. Pasireotide 300 µg bid was administered and uptitrated to 600 µg bid. Treatment was well tolerated, achieving dramatic improvement of clinical picture with progressive normalization of serum cortisol and ACTH levels as well as UFC. After 4 months, the patient underwent successful heart transplantation. Many complications ensued and were overcome. Pituitary MRI was negative. On pasireotide 300 µg bid and prednisone 2.5 mg/day (as part of immunosuppressive therapy), morning serum cortisol and ACTH were 15.6 µg/dL and 54 pg/mL respectively, UFC was 37 µg/24 h, fasting glucose: 107 mg/dL and HbA1c: 6.5%. In conclusion, primary treatment with pasireotide achieved remission of hypercortisolism, thus allowing the patient to undergo heart transplantation.

Learning points:

  • Untreated Cushing’s syndrome is associated with ominous prognosis.

  • First-line treatment is surgery (at pituitary or adrenal, according to disease localization).

  • A few drugs are available to treat hypercortisolism.

  • Pasireotide is a multi-ligand somatostatin analog approved for treatment of hypercortisolism.

  • Primary treatment with pasireotide was effective in a patient with severe Cushing’s syndrome, allowing him to undergo heart transplantation.

Open access

Marisa M Fisher, Susanne M Cabrera and Erik A Imel

Summary

Neonatal severe hyperparathyroidism (NSHPT) is a rare disorder caused by inactivating calcium-sensing receptor (CASR) mutations that result in life-threatening hypercalcemia and metabolic bone disease. Until recently, therapy has been surgical parathyroidectomy. Three previous case reports have shown successful medical management of NSHPT with cinacalcet. Here we present the detailed description of two unrelated patients with NSHPT due to heterozygous R185Q CASR mutations. Patient 1 was diagnosed at 11 months of age and had developmental delays, dysphagia, bell-shaped chest, and periosteal bone reactions. Patient 2 was diagnosed at 1 month of age and had failure to thrive, osteopenia, and multiple rib fractures. Cinacalcet was initiated at 13 months of age in patient 1, and at 4 months of age in patient 2. We have successfully normalized their parathyroid hormone and alkaline phosphatase levels. Despite the continuance of mild hypercalcemia (11–12 mg/dl), both patients showed no hypercalcemic symptoms. Importantly, patient 1 had improved neurodevelopment and patient 2 never experienced any developmental delays after starting cinacalcet. Neither experienced fractures after starting cinacalcet. Both have been successfully managed long-term without any significant adverse events. These cases expand the current literature of cinacalcet use in NSHPT to five successful reported cases. We propose that cinacalcet may be considered as an option for treating the severe hypercalcemia and metabolic bone disease found in infants and children with inactivating CASR disorders.

Learning points

  • NSHPT due to mutations in the CASR gene occurs with hypercalcemia and metabolic bone disease, but not always with severe critical illness in infancy.

  • NSHPT should be considered in the differential diagnosis for a newborn with a bell-shaped chest, osteopenia, and periosteal reactions.

  • Neurodevelopmental consequences may occur in children with hypercalcemia and may improve during treatment.

  • Calcimimetics can be used to successfully treat the pathophysiology of NSHPT directly to control serum calcium levels.